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Öğe Design and Synthesis of ?-O-Glucosylated 5-(Arylidene)-6-Aminouracils: Towards Water-Soluble 8-Aryl Xanthines as Effective Enzyme Inhibitors(Wiley-V C H Verlag Gmbh, 2024) Poslu, Ayse Halic; Ertik, Onur; Abul, Nurgul; Telli, Fatma Cetin; Gulcin, Ilhami; Koz, Omer; Koz, Gamze8-Aryl xanthines are selective enzyme inhibitors modified from naturally occurring methylxanthines. However, the low water solubility of substituted xanthines restricts their clinical applications. We developed a strategy to improve the water solubility of biologically privileged 8-aryl xanthines. A series of glucosylated 5-(arylidene)-6-aminouracil was synthesized as 8-aryl-1,3-dimethyl xanthine precursors and fully characterized with spectroscopic methods. Koenigs-Knorr reaction was used to synthesize beta-O-glucosylated aromatic aldehydes which were then reacted with 5,6-diamino-1,3-dimethyluracil to obtain the corresponding 5-(arylidene)-6-aminouracils. The strategy was validated by the ring-closing reaction of a beta-O-glucosylated 5-(arylidene)-6-aminouracil derivative with iodine (I-2) in dimethoxyethane. The water solubility of the glucosylated 8-aryl-1,3-dimethyl xanthine and its non-glycosylated counterpart was compared. Glucosylation improved the water solubility of the compound. The effect of glucosylation on the bioactivity of the compounds was investigated by measuring their inhibition effect on some common enzymes. The glucosylated 8-aryl xanthine demonstrated significantly better efficiency. Molecular docking was performed to elucidate the ligand-protein interactions. Since the target enzymes are primarily related to brain disorders, the blood-brain barrier (BBB) penetration ability of 8-aryl xanthine partners was investigated. According to adsorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions, glucosylated 8-aryl xanthine was found to be BBB permeable.Öğe Structural characterization and biological evaluation of uracil-appended benzylic amines as acetylcholinesterase and carbonic anhydrase I and II inhibitors(Elsevier, 2023) Bulut, Zafer; Abul, Nurgul; Poslu, Ayse Halic; Gulcin, Ilhami; Ece, Abdulilah; Ercag, Erol; Koz, GamzeA series of novel uracil-appended benzylic amines were synthesized through reductive amination with moderate to good yields (30-84% yields). In situ prepared 5-(arylidene)-6-aminouracils with the condensation reaction between 5,6-diamino-1,3-dimethyluracil and substituted salicylaldehydes were reduced by excess sodium borohydride. All of the compounds were characterized using FT-IR, H-1 NMR, C-13 NMR spectroscopy and elemental analysis. The inhibition abilities of novel uracil-appended benzylic amines (1-9) were evaluated against acetylcholinesterase (AChE) and human carbonic anhydrase I and II (hCA I and II) isoenzymes that are linked to some global disorders such as Alzheimer's disease (AD), epilepsy, diabetes and glaucoma. The compounds exhibited inhibition profiles with K-i values ranging from 2.28 +/- 0.41 nM to 5.25 +/- 0.75 nM for AChE, 36.10 +/- 5.22-110.31 +/- 54.81 nM for hCA I and 16.33 +/- 4.91-72.03 +/- 28.86 for hCA II. Tacrine was used as a reference inhibitor for AChE and exhibited a K-i value of 2.59 +/- 0.92 nM against the AChE enzyme. On the other hand, Acetazolamide was used as a standard inhibitor towards hCA I and hCA II isoforms with K-i values of 31.38 +/- 8.56 nM and 18.72 +/- 1.67 nM, respectively. The results of enzyme inhibition associated with some global metabolic diseases indicate that novel uracil-appended benzylic amines may have the potential to develop new drugs to treat some common diseases such as Alzheimer's disease (AD), epilepsy and glaucoma. Molecular docking simulations were conducted to explain the binding interactions of compounds with AChE, hCA I and hCA II. Pharmacokinetic profiles were predicted to be within the acceptable ranges. (c) 2023 Elsevier B.V. All rights reserved.Öğe Structural characterization, cytotoxic and enzyme inhibitory profile of a novel triazole-linked ferrocene hybrid of 18?-glycyrrhetinic acid(Pergamon-Elsevier Science Ltd, 2025) Ozturk, Zehra; Yildiz, Yaren; Abul, Nurgul; Ertik, Onur; Ari, Ferda; Gulcin, Ilhami; Koz, Gamze18 beta-Glycyrrhetinic acid (GA) is a pentacyclic triterpene which was obtained from the roots of Glycyrrhiza glabra known for its diverse pharmaceutical applications. The primary aim of this study is to enhance the pharmaceutical properties of GA by modifying it with a 1,2,3-triazole-functionalized ferrocene moiety. The hybrid compound 3 was synthesized by amide functionalization of GA at the C-30 position with ferrocene, linked via a 1,4-disubstituted 1,2,3-triazole bridge. Additionally, the C-3 hydroxyl group of GA was converted into an acetyl ester. The hybrid compound 3 was characterized using FT-IR, NMR (1H and 13C) and HR-MS. The aim of the modification was to enhance the cytotoxic and enzyme inhibitory effects of GA. 1,2,3,-Triazole substituted ferrocene (1), C-3 acetylated GA and the hybrid compound 3 were tested on A549, MCF-7, HCT-116, and PC-3 cancer cell lines. MCF-7 and HCT-116 cells showed the highest sensitivity to the compounds. Compound 3 showed more cytotoxicity than both GA and compound 1 with IC50 values of 23.97 and 50 mu M in MCF-7 and HCT-116 cells, respectively. Morphological analysis indicated that compound 3 induced apoptotic cell death. In addition, the inhibitory effect of compounds on carbonic anhydrase I-II isoenzymes (hCAI-II), acetylcholinesterase/butyrylcholinesterase (AChE/BChE) enzymes, and alpha-glucosidase was tested. According to the results, compound 3, exhibited the strongest inhibitory properties for all enzymes tested with IC50 values of 0.0323, 0.3058, 0.0078, 0.0090 and 0.0120 mu M, respectively. Molecular docking studies were performed to investigate the ligand-target protein interactions. Incorporating an organometallic sandwich-like compound ferrocene into GA via a 1,2,3-triazole bridge appears to be an effective strategy for modifying and enhancing its bioactivity.
